{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T01:25:15Z","timestamp":1790990715075,"version":"4.1.0"},"reference-count":68,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"753","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2024,6,26]]},"abstract":"<jats:p>\n                    Congenital pseudarthrosis of the tibia (CPT) is a severe pathology marked by spontaneous bone fractures that fail to heal, leading to fibrous nonunion. Half of patients with CPT are affected by the multisystemic genetic disorder neurofibromatosis type 1 (NF1) caused by mutations in the\n                    <jats:italic>NF1<\/jats:italic>\n                    tumor suppressor gene, a negative regulator of RAS\u2013mitogen-activated protein kinase (MAPK) signaling pathway. Here, we analyzed patients with CPT and\n                    <jats:italic>Prss56-Nf1<\/jats:italic>\n                    knockout mice to elucidate the pathogenic mechanisms of CPT-related fibrous nonunion and explored a pharmacological approach to treat CPT. We identified\n                    <jats:italic>NF1<\/jats:italic>\n                    -deficient Schwann cells and skeletal stem\/progenitor cells (SSPCs) in pathological periosteum as affected cell types driving fibrosis. Whereas\n                    <jats:italic>NF1<\/jats:italic>\n                    -deficient SSPCs adopted a fibrotic fate,\n                    <jats:italic>NF1<\/jats:italic>\n                    -deficient Schwann cells produced critical paracrine factors including transforming growth factor\u2013\u03b2 and induced fibrotic differentiation of wild-type SSPCs. To counteract the elevated RAS-MAPK signaling in both\n                    <jats:italic>NF1<\/jats:italic>\n                    -deficient Schwann cells and SSPCs, we used MAPK kinase (MEK) and Src homology 2 containing protein tyrosine phosphatase 2 (SHP2) inhibitors. Combined MEK-SHP2 inhibition in vivo prevented fibrous nonunion in the\n                    <jats:italic>Prss56-Nf1<\/jats:italic>\n                    knockout mouse model, providing a promising therapeutic strategy for the treatment of fibrous nonunion in CPT.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adj1597","type":"journal-article","created":{"date-parts":[[2024,6,26]],"date-time":"2024-06-26T13:59:57Z","timestamp":1719410397000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":12,"title":["MEK-SHP2 inhibition prevents tibial pseudarthrosis caused by\n                    <i>NF1<\/i>\n                    loss in Schwann cells and skeletal stem\/progenitor cells"],"prefix":"10.1126","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3598-2617","authenticated-orcid":true,"given":"Simon","family":"Perrin","sequence":"first","affiliation":[{"name":"Universit\u00e9 Paris Est Creteil, INSERM, IMRB, 94000 Creteil, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanela","family":"Protic","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Est Creteil, INSERM, IMRB, 94000 Creteil, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"Bretegnier","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Est Creteil, INSERM, IMRB, 94000 Creteil, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-5437-0015","authenticated-orcid":true,"given":"Ingrid","family":"Laurendeau","sequence":"additional","affiliation":[{"name":"INSERM UMR S1016, Institut Cochin, Universit\u00e9 Paris Cit\u00e9, 75014 Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oriane Duchamp","family":"de Lageneste","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Est Creteil, INSERM, IMRB, 94000 Creteil, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4383-5593","authenticated-orcid":true,"given":"Nicolas","family":"Panara","sequence":"additional","affiliation":[{"name":"INSERM UMR S1016, Institut Cochin, Universit\u00e9 Paris Cit\u00e9, 75014 Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2289-6257","authenticated-orcid":true,"given":"Odile","family":"Ruckebusch","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Est Creteil, INSERM, IMRB, Plateforme de Cytom\u00e9trie en flux, 94000 Creteil, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marine","family":"Luka","sequence":"additional","affiliation":[{"name":"Paris Cit\u00e9 University, Imagine Institute, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, INSERM UMR 1163, 75015 Paris, France."},{"name":"Labtech Single-Cell@Imagine, Imagine Institute, INSERM UMR 1163, 75015 Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7870-7821","authenticated-orcid":true,"given":"C\u00e9cile","family":"Masson","sequence":"additional","affiliation":[{"name":"Bioinformatics Core Facility, Institut Imagine-Structure F\u00e9d\u00e9rative de Recherche Necker, INSERM U1163, 75015 Paris, France."},{"name":"INSERM US24\/CNRS UAR3633, Paris Cit\u00e9 University, 75015 Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7812-0320","authenticated-orcid":true,"given":"Th\u00e9odora","family":"Maillard","sequence":"additional","affiliation":[{"name":"Service de M\u00e9decine G\u00e9nomique des Maladies de Syst\u00e8me et d'Organe, H\u00f4pital Cochin, DMU BioPhyGen, Assistance Publique-H\u00f4pitaux de Paris, AP-HP, Centre-Universit\u00e9 Paris Cit\u00e9, F-75014 Paris, 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France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mickael","family":"M\u00e9nager","sequence":"additional","affiliation":[{"name":"Paris Cit\u00e9 University, Imagine Institute, Laboratory of Inflammatory Responses and Transcriptomic Networks in Diseases, Atip-Avenir Team, INSERM UMR 1163, 75015 Paris, France."},{"name":"Labtech Single-Cell@Imagine, Imagine Institute, INSERM UMR 1163, 75015 Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4777-1387","authenticated-orcid":true,"given":"Dominique","family":"Vidaud","sequence":"additional","affiliation":[{"name":"INSERM UMR S1016, Institut Cochin, Universit\u00e9 Paris Cit\u00e9, 75014 Paris, France."},{"name":"Service de M\u00e9decine G\u00e9nomique des Maladies de Syst\u00e8me et d'Organe, H\u00f4pital Cochin, DMU BioPhyGen, Assistance Publique-H\u00f4pitaux de Paris, AP-HP, Centre-Universit\u00e9 Paris Cit\u00e9, F-75014 Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7381-6770","authenticated-orcid":true,"given":"Piotr","family":"Topilko","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Est Creteil, INSERM, IMRB, 94000 Creteil, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2964-8666","authenticated-orcid":true,"given":"B\u00e9atrice","family":"Parfait","sequence":"additional","affiliation":[{"name":"INSERM UMR S1016, Institut Cochin, Universit\u00e9 Paris Cit\u00e9, 75014 Paris, France."},{"name":"Service de M\u00e9decine G\u00e9nomique des Maladies de Syst\u00e8me et d'Organe, H\u00f4pital Cochin, DMU BioPhyGen, Assistance Publique-H\u00f4pitaux de Paris, AP-HP, Centre-Universit\u00e9 Paris Cit\u00e9, F-75014 Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8423-8718","authenticated-orcid":true,"given":"C\u00e9line","family":"Colnot","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Est Creteil, INSERM, IMRB, 94000 Creteil, 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Perrin, C.-A. Wotawa, V. Bretegnier, M. Luka, F. Coulpier, C. Masson, M. M\u00e9nager, C. 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